We have previously sequenced the exomes of individuals from four families, where at least one member is affected with Moebius syndrome. Each family unit consists of the affected individual(s), non-affected parents, and in some cases, non-affected siblings. We identified a few candidate genes (1-3) per family that have variants segregating with Moebius syndrome (i.e. in affected family members and not in the non-affecteds). The genes identified do not overlap with any of the published candidate genes. Notably, we have not identified candidate genes in common across two or more of the four families studied. It is clear that interrogating more homogeneous subgroups of affected individuals based on detailed clinical phenotyping is required given the complexity and heterogeneity of this disorder to identify common genetic and potential environmental factors. During the past year, we established a new NHGRI protocol (14-HG-0055; PI: Irini Manoli) dedicated to defining the phenotypes and the genetic factors associated with Moebius syndrome and other congenital facial weakness disorders. This protocol is partially funded by a competitive UO1 grant awarded in January 2014, 1U01HD079068-01 (coPIs: Jabs, Engle, Manoli, Brooks, Pierpaoli). We will enroll 24 patients and their family members each year, for the next 3 years. The affected individual(s) from each family will undergo extensive phenotyping at the NIH clinical research center. Specialists in ophthalmology, neurology, audiology, otolaryngology, dentistry, craniofacial surgery, speech pathology and rehabilitation medicine will evaluate the study participants. To date, we have enrolled 37 patients and their family members and have received several more inquiries at the 2015 Moebius Syndrome Foundation conference in Bethesda. We are prioritizing families with more than one affected individual, since we believe these will provide a better chance of identifying a causative germline mutation. Each of the three teams collaborating under the UO1 grant (NIH: Manoli/Brooks/Pierpaoli; MSMC: Jabs; BCH: Engle) will analyze both the clinical and genetic data. We have created a database to enable sharing of the clinical phenotype information. The detailed phenotype information have already allowed us to categorize the affected individuals into more clearly defined subgroups, which will help inform and direct the genetic analyses that are currently in progress. The genetic data generated at the NIH is analyzed by all of the collaborating groups using various strategies and variants will be screened in the cohorts collected by our collaborators at MSMC and BCH. We have also received a body donation of an individual with classic Moebius syndrome. Brainstem tissue from this cadaver will be an invaluable resource, as it will enable investigations into potential somatic mutations contributing to Moebius syndrome. We believe this collaborative approach of bringing together expert investigators from multiple sites to combine valuable resources/data, will maximize our capacity to identify germline or somatic genetic causes of the various syndromes associated with facial palsy. Our collaboration have recently extended to include other investigators of facial weakness disorders and these interaction have contributed to the identification of a gene in which mutations are likely to be causative for Carey-Fineman-Ziter Syndrome.